Substituted amphetamines, such as methamphetamine (METH), produce long-lasting, partial loss of central monoamine systems. The postsynaptic consequences of the such loss on basal ganglia function, however, are less well known. Preliminary data from our laboratory suggest that the expression of the NR2A subunit of the NMDA receptor (NMDAR) is increased throughout the striaturn 3 weeks following a neurotoxic regimen of METH. The NMDAR is comprised of an NR1 subunit and any of four NR2 subunits (NR2A-D), which confer different properties to the receptor. Whereas the NR2B subunit is expressed at uniform levels throughout striaturn the NR2A subunit, displays greater expression laterally. We have shown that the greater NR2A subunit expression in lateral striatum is associated with NMDAR-mediated excitatory postsynaptic currents (EPSCs) with faster kinetics than those in medial striatum. Others have demonstrated and inability to induce NMDAR-dependent long-term porentiation (LTP) in dorsolateral, but not dorsomedial, striatum. Thus, the level of expression of the NR2A subunit determines NMDAR function in striatum. Thus, this proposal will test the hypothesis that increases in NR2A subunit expression induced by a neurotoxic regimen of METH will alter NMDAR function. This will be accomplished by completing the following specific aims: A) Determine the functional impact of METH-induced changes in NR2A subunit expression on NMDAR-mediated EPSCs in dorsolateral and ventromedial striatum. B) Examine the functional consequences of METH-induced changes in the monoamines and NR2A subunit expression on striatal LTP. The results of these studies will further elucidate postsynaptic changes associated with METH neurotoxicity, and will provide molecular insight into the behavioral and cognitive alterations which ensue a neurotoxic insult induced by METH.